WO2020052631A1 - Composés de triazolo-pyrimidine et leurs utilisations - Google Patents

Composés de triazolo-pyrimidine et leurs utilisations Download PDF

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Publication number
WO2020052631A1
WO2020052631A1 PCT/CN2019/105591 CN2019105591W WO2020052631A1 WO 2020052631 A1 WO2020052631 A1 WO 2020052631A1 CN 2019105591 W CN2019105591 W CN 2019105591W WO 2020052631 A1 WO2020052631 A1 WO 2020052631A1
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Prior art keywords
methyl
pyrimidin
triazolo
amino
alkyl
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PCT/CN2019/105591
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English (en)
Inventor
Qingbei Zeng
Changhe Qi
Honchung TSUI
Zhenfan YANG
Xiaolin Zhang
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Dizal (Jiangsu) Pharmaceutical Co., Ltd.
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Priority to CA3111869A priority Critical patent/CA3111869A1/fr
Priority to CN202010656938.4A priority patent/CN111635408B/zh
Priority to BR112021004774-3A priority patent/BR112021004774A2/pt
Priority to CN201980006436.2A priority patent/CN111601809A/zh
Priority to CN202010657655.1A priority patent/CN112279852B/zh
Priority to EP19859380.8A priority patent/EP3849983A4/fr
Priority to AU2019340767A priority patent/AU2019340767A1/en
Priority to KR1020217010809A priority patent/KR20210075996A/ko
Application filed by Dizal (Jiangsu) Pharmaceutical Co., Ltd. filed Critical Dizal (Jiangsu) Pharmaceutical Co., Ltd.
Priority to MX2021002998A priority patent/MX2021002998A/es
Priority to JP2021513827A priority patent/JP2022500402A/ja
Publication of WO2020052631A1 publication Critical patent/WO2020052631A1/fr
Priority to US16/910,334 priority patent/US10858365B2/en
Priority to US17/027,740 priority patent/US11629147B2/en
Priority to ZA2021/01658A priority patent/ZA202101658B/en

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    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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    • A—HUMAN NECESSITIES
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds thereof

Definitions

  • the present disclosure relates to novel triazolo-pyrimidine compounds targeting adenosine receptors (especially A1 and A2, particularly A2a) .
  • the present disclosure also relates to pharmaceutical compositions comprising one or more of the compounds as an active ingredient, and use of the compounds in the treatment of adenosine receptor (AR) associated diseases, for example cancer such as non-small cell lung cancer (NSCLC) , renal cell carcinoma (RCC) , prostate cancer, and breast cancer.
  • NSCLC non-small cell lung cancer
  • RCC renal cell carcinoma
  • Adenosine is a naturally occurring nucleoside, which elicits a variety of physiological responses by interacting with a family of adenosine receptors.
  • adenosine receptors Four subtypes of adenosine receptors (A1, A2a, A2b, and A3) in humans have been differentiated based on their biochemical and pharmacological properties such as ligand binding characteristics, glycosylations, and functions.
  • the inflammatory response helps eliminate harmful agents from the body, but inflammation is also a non-specific response that can harm healthy tissue.
  • pathogenic insults that can initiate an inflammatory response including infection, allergens, autoimmune stimuli, immune response to transplanted tissue, noxious chemicals, and toxins, ischemia/reperfusion, hypoxia, mechanical and thermal trauma, as well as growth of tumors.
  • Adenosine receptors play a non-redundant role in down-regulation of inflammation in vivo by acting as a physiological "STOP" (a termination mechanism) that can limit the immune response and thereby protect normal tissues form excessive immune damage during pathogenesis of different diseases.
  • Adenosine receptors such as A2a, A2b, and A3, are shown to down-regulate the immune response during inflammation and protect tissues from immune damage. Inhibition of signaling through the adenosine receptor can be used to intensify and prolong the immune response. Adenosine suppresses prolonged inflammation acting through the A2a adenosine receptor (Ohta et al., Nature 2001; 414: 916-920) .
  • A2b adenosine receptor has been implicated in regulation of cell growth (See Adenosine A2b Receptors as Therapeutic Targets, Drug Dev Res 45: 198; Feoktistov et al., Trends Pharmacol Sci 19: 148-153) .
  • Adenosine receptor-associated disease such as cancer (e.g., NSCLC, RCC, prostate cancer, or breast cancer) , Parkinson disease, epilepsy, cerebral ischemia and stroke, depression, cognitive impairment, HIV, ADA-SCID, AHF and chronic heart failure, chronic obstructive pulmonary disease (COPD) , or asthma.
  • cancer e.g., NSCLC, RCC, prostate cancer, or breast cancer
  • Parkinson disease e.g., epilepsy, cerebral ischemia and stroke, depression, cognitive impairment, HIV, ADA-SCID, AHF and chronic heart failure, chronic obstructive pulmonary disease (COPD) , or asthma.
  • COPD chronic obstructive pulmonary disease
  • the present disclosure provides a compound represented by Formula (I) :
  • the present disclosure provides a compound represented by Formula (Ia) :
  • ring A, ring B, ring Q, W, R 1 , R 2 , R 3 , m, n and i are as herein defined.
  • the present disclosure provides a compound represented by Formula (Ib) :
  • the present disclosure also relates to pharmaceutical compositions comprising one or more of the compounds, or a pharmaceutically acceptable salt thereof, as an active ingredient, and use of the compounds, or a pharmaceutically acceptable salt thereof, in the treatment of adenosine receptors (AR) associated diseases, for example cancer such as NSCLC, RCC, prostate cancer, or breast cancer.
  • AR adenosine receptors
  • the present disclosure provides compounds of Formula (I) :
  • X is selected from amino, halogen, hydroxyl, cyano, C 1-12 alkoxyl, N- (C 1-12 alkyl) amino, N, N- (C 1-12 alkyl) 2 amino, C 1-12 alkanoylamino,
  • ring A is 3-12 membered saturated or unsaturated mono-or poly-cyclic heterocyclyl
  • Y is -W-V, wherein -W-is bond, O, S, -NH-, -C 1-12 alkylene-, -C 1-12 alkylene-NH-, V is hydrogen, C 1-12 alkyl, C 1-12 alkoxyl, C 1-12 alkyl-OH, amino, carbamoyl, urea, carbamate, N- (C 1-12 alkyl) amino, N, N- (C 1-12 alkyl) 2 amino, N- (C 1-12 alkyl) carbamoyl, N, N- (C 1-12 alkyl) 2 carbamoyl, C 1-12 alkanoylamino, 3-12 membered saturated or unsaturated carbocyclyl, or 3-12 membered saturated or unsaturated heterocyclyl, which can be optionally mono-or independently multi-substituted by R 3 ,
  • Z is selected from hydrogen, halogen, cyano, hydroxyl, amino, carbamoyl, urea, carbamate, C 1-12 alkyl, N- (C 1-12 alkyl) amino, N, N- (C 1-12 alkyl) 2 amino, 3-12 membered saturated or unsaturated carbocyclyl, or 3-12 membered saturated or unsaturated heterocyclyl, which can be optionally mono-or independently multi-substituted by R 2 ,
  • each R 1 is independently selected from halogen, hydroxyl, cyano, amino, carbamoyl, urea, carbamate, C 1-12 alkyl, C 1-12 haloalkyl, C 1-12 alkoxyl, C 1-12 haloalkoxyl, C 1-12 alkyl-OH, N- (C 1-12 alkyl) amino, N, N- (C 1-12 alkyl) 2 amino, N- (C 1-12 alkyl) carbamoyl, N, N- (C 1-12 alkyl) 2 carbamoyl, C 1-12 alkanoylamino, a 3-10 membered saturated or unsaturated carbocyclyl, or a 3-10 membered saturated or unsaturated heterocyclyl, wherein said 3-10 membered saturated or unsaturated carbocyclyl, or 3-10 membered saturated or unsaturated heterocyclyl can be optionally mono-or independently multi-substituted by R 4 ,
  • each R 2 is independently selected from halogen, hydroxyl, cyano, amino, carbamoyl, urea, carbamate, C 1-12 alkyl, C 1-12 haloalkyl, C 1-12 alkoxyl, C 1-12 haloalkoxyl, C 1-12 alkyl-OH, N- (C 1-12 alkyl) amino, N, N- (C 1-12 alkyl) 2 amino, N- (C 1-12 alkyl) carbamoyl, N, N- (C 1-12 alkyl) 2 carbamoyl, C 1-12 alkanoylamino, a 3-10 membered saturated or unsaturated carbocyclyl, or a 3-10 membered saturated or unsaturated heterocyclyl, wherein said 3-10 membered saturated or unsaturated carbocyclyl, or 3-10 membered saturated or unsaturated heterocyclyl can be optionally mono-or independently multi-substituted by R 5 ,
  • each R 3 is independently selected from halogen, hydroxyl, cyano, amino, carbamoyl, urea, carbamate, C 1-12 alkyl, C 1-12 haloalkyl, C 1-12 alkoxyl, C 1-12 haloalkoxyl, C 1-12 alkyl-OH, N- (C 1-12 alkyl) amino, N, N- (C 1-12 alkyl) 2 amino, N- (C 1-12 alkyl) carbamoyl, N, N- (C 1-12 alkyl) 2 carbamoyl, C 1-12 alkanoylamino, a 3-10 membered saturated or unsaturated carbocyclyl, or a 3-10 membered saturated or unsaturated heterocyclyl, wherein said 3-10 membered saturated or unsaturated carbocyclyl, or 3-10 membered saturated or unsaturated heterocyclyl can be optionally mono-or independently multi-substituted by R 6 ,
  • each R 4 , R 5 or R 6 is independently selected from halogen, hydroxyl, cyano, amino, carbamoyl, urea, carbamate, C 1-12 alkyl, C 1-12 haloalkyl, C 1-12 alkoxyl, C 1-12 haloalkoxyl, C 1-12 alkyl-OH, N- (C 1-12 alkyl) amino, N, N- (C 1-12 alkyl) 2 amino, N- (C 1-12 alkyl) carbamoyl, N, N- (C 1-12 alkyl) 2 carbamoyl, C 1-12 alkanoylamino,
  • n 0, 1, 2, 3 or 4.
  • X is selected from amino, halogen, hydroxyl, cyano, C 1-12 alkoxyl, N- (C 1-12 alkyl) amino, N, N- (C 1-12 alkyl) 2 amino, or C 1-12 alkanoylamino.
  • X is amino
  • ring A is 3-12 membered saturated or unsaturated mono-or poly-cyclic heterocyclyl having 1, 2, or 3 heteroatoms selected from N, O, or S.
  • ring A is 6-10 membered unsaturated mono-or poly-cyclic heterocyclyl selected from the group consisting of pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, pyridonyl, pyrimidonyl, pyrazinonyl, pyrimidonyl, pyridazonyl, triazinonyl, phenyl fused ring or pyridinyl fused ring.
  • ring A is 6-10 membered unsaturated mono-or poly-cyclic heterocyclyl selected from
  • each R 1 is independently selected from: halogen, cyano, amino, carbamoyl, urea, carbamate, C 1-12 alkyl, C 1-12 haloalkyl, C 1-12 alkoxyl, C 1-12 haloalkoxyl, C 1-12 alkyl-OH, N- (C 1-12 alkyl) amino, N, N- (C 1-12 alkyl) 2 amino, N- (C 1-12 alkyl) carbamoyl, N, N- (C 1-12 alkyl) 2 carbamoyl, or 3-6 membered saturated carbocyclyl or heterocyclyl.
  • the 3-6 membered saturated carbocyclyl or heterocyclyl is cyclopropyl, cyclobutyl, oxacyclopentanyl, oxetanyl, or 1, 1-dioxothietanyl.
  • m is 0.
  • m is 1.
  • n is 2.
  • m is 3.
  • m is 4.
  • Y is -W-V.
  • -W- is methylene or ethylene.
  • -W- is methylene
  • V is halogen, C 1-12 alkyl, C 1-12 alkoxyl, C 1-12 alkyl-OH, amino, carbamoyl, urea, carbamate, N- (C 1-12 alkyl) amino, N, N- (C 1-12 alkyl) 2 amino, N- (C 1-12 alkyl) carbamoyl, N, N- (C 1-12 alkyl) 2 carbamoyl, C 1-12 alkanoylamino, which can be optionally mono-or independently multi-substituted by R 3 .
  • V is 5-6 membered saturated or unsaturated carbocyclyl, or 5-6 membered saturated or unsaturated heterocyclyl, which can be optionally mono-or independently multi-substituted by R 3 .
  • V is 5-6 membered saturated or unsaturated carbocyclyl, or 5-6 membered saturated or unsaturated heterocyclyl selected from:
  • V is pyrrolidyl, tetrahydrofuryl, thienyl, triazolyl, thiazolyl, phenyl, or pyridinyl, which can be optionally mono-or independently multi-substituted by R 3 .
  • each R 3 is independently selected from halogen, cyano, amino, C 1-12 alkyl, C 1-12 alkoxyl, C 1-12 haloalkoxyl, N- (C 1-12 alkyl) amino, N, N- (C 1-12 alkyl) 2 amino, C 1-12 alkanoylamino, a 3-10 membered saturated or unsaturated carbocyclyl, or a 3-10 membered saturated or unsaturated heterocyclyl, wherein the 3-10 membered saturated or unsaturated carbocyclyl, or 3-10 membered saturated or unsaturated heterocyclyl can be optionally mono-or independently multi-substituted by R 6 .
  • V is C 1-12 alkoxyl
  • V is C 1-12 alkyl which is further substituted by C 1-12 alkoxyl.
  • -W- is ethylene
  • V is methoxyl
  • V is pyrrolidyl, tetrahydrofuryl, thienyl, triazolyl, thiazolyl, phenyl, or pyridinyl, which can be optionally mono-or independently multi-substituted by R 3 , wherein each R 3 is independently selected from halogen, cyano, amino, C 1-12 alkyl, C 1-12 alkoxyl, C 1-12 haloalkoxyl, N- (C 1-12 alkyl) amino, N, N- (C 1-12 alkyl) 2 amino, C 1-12 alkanoylamino.
  • Z is hydrogen, halogen, cyano, hydroxyl, amino, carbamoyl, urea, carbamate, N- (C 1-12 alkyl) amino, N, N- (C 1-12 alkyl) 2 amino, C 1-12 alkyl, 3-12 membered saturated or unsaturated carbocyclyl, or 3-12 membered saturated or unsaturated heterocyclyl which can be optionally mono-or independently multi-substituted by R 2 , wherein each R 2 is independently selected from halogen, cyano, C 1-12 alkyl, C 1-12 haloalkyl, C 1-12 alkoxyl, or C 1-12 haloalkoxyl.
  • Z is halogen, amino, N- (C 1-12 alkyl) amino, or N, N- (C 1-12 alkyl) 2 amino.
  • Z is 3-12 membered saturated or unsaturated carbocyclyl, or 3-12 membered saturated or unsaturated heterocyclyl which can be optionally mono-or independently multi-substituted by R 2 .
  • Z is 3-12 membered saturated or unsaturated carbocyclyl, or 3-12 membered saturated or unsaturated heterocyclyl selected from:
  • each R 2 is independently selected from halogen, cyano, C 1-12 alkyl, C 1-12 haloalkyl, C 1-12 alkoxyl, or C 1-12 haloalkoxyl.
  • ring A is 6-10 membered unsaturated mono-or poly-cyclic heterocyclyl having 1, 2, or 3 heteroatoms selected from N, O, or S;
  • ring B is selected from 3-12 membered saturate saturated or unsaturated carbocyclyl, or 3-12 membered saturated or unsaturated heterocyclyl;
  • ring Q is 5-6 membered saturated or unsaturated carbocyclyl, or 5-6 membered saturated or unsaturated heterocyclyl;
  • W is bond, O, S, -NH-, C 1-12 alkylene, or C 1-12 alkylene-NH-,
  • each R 1 is independently selected from halogen, hydroxyl, cyano, amino, C 1-12 alkyl, C 1-12 haloalkyl, C 1-12 alkoxyl, C 1-12 haloalkoxyl, C 1-12 alkyl-OH, N- (C 1-12 alkyl) amino, N, N- (C 1-12 alkyl) 2 amino, carbamoyl, N- (C 1-12 alkyl) carbamoyl, N, N- (C 1-12 alkyl) 2 carbamoyl, a 3-10 membered saturated or unsaturated carbocyclyl, or a 3-10 membered saturated or unsaturated heterocyclyl, wherein said 3-10 membered saturated or unsaturated carbocyclyl, or 3-10 membered saturated or unsaturated heterocyclyl can be optionally mono-or independently multi-substituted by R 4 ;
  • each R 2 is independently selected from halogen, hydroxyl, cyano, amino, C 1-12 alkyl, C 1-12 haloalkyl, C 1-12 alkoxyl, C 1-12 haloalkoxyl, C 1-12 alkyl-OH, N- (C 1-12 alkyl) amino, N, N- (C 1-12 alkyl) 2 amino, carbamoyl, N- (C 1-12 alkyl) carbamoyl, N, N- (C 1-12 alkyl) 2 carbamoyl;
  • each R 3 is independently selected from halogen, hydroxyl, cyano, amino, C 1-12 alkyl, C 1-12 haloalkyl, C 1-12 alkoxyl, C 1-12 haloalkoxyl, C 1-12 alkyl-OH, N- (C 1-12 alkyl) amino, N, N- (C 1-12 alkyl) 2 amino, carbamoyl, N- (C 1-12 alkyl) carbamoyl, N, N- (C 1-12 alkyl) 2 carbamoyl;
  • each R 4 is independently selected from halogen, hydroxyl, cyano, amino, carbamoyl, urea, carbamate, C 1-12 alkyl, C 1-12 haloalkyl, C 1-12 alkoxyl, C 1-12 haloalkoxyl, C 1-12 alkyl-OH, N- (C 1-12 alkyl) amino, N, N- (C 1-12 alkyl) 2 amino, carbamoyl, N- (C 1-12 alkyl) carbamoyl, N, N- (C 1-12 alkyl) 2 carbamoyl, C 1-12 alkanoylamino;
  • n 0, 1, 2, 3 or 4;
  • n 0, 1, 2, 3 or 4;
  • i 0, 1, 2, 3 or 4.
  • ring A is selected from
  • ring A is selected from the group consisting of: 4-pyridinyl, 4-pyridazinyl, 5-pyridinyl-2-one, imidazo [1, 2-a] pyridin-6-yl, [1, 2, 4] triazolo [4, 3-a] pyridin-6-yl, 6-benzimidazolyl, 6-benzthiazolyl, quinolin-6-yl, or quinoxalin-6-yl.
  • each R 1 is independently selected from hydroxyl, fluoro, chloro, bromo, amino, carbamoyl, urea, carbamate, cyano, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, methoxyl, ethoxyl, difluoromethoxyl, trifluoromethoxyl, trifluoroethoxyl, methylamino, dimethylamino, ethylamino, isopropanylamino, hydroxymethyl, hydroxyethyl, cyclopropyl, cyclobutyl, 3-oxacyclopentanyl, 3-oxetanyl, or 1, 1-dioxothietanyl, which can be optionally further mono-or independently multi-substituted by R 4 .
  • one of R 1 is selected from cyclopropyl, cyclobutyl, tetrahydrofuryl, oxetanyl, or 1, 1-dioxothietanyl, which can be optionally mono-or independently multi-substituted by R 4 .
  • m is 0, 1 or 2.
  • each R 1 is independently selected from: hydroxyl, fluoro, chloro, bromo, amino, carbamoyl, urea, carbamate, cyano, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, methoxyl, ethoxyl, difluoromethoxyl, trifluoromethoxyl, trifluoroethoxyl, methylamino, dimethylamino, ethylamino, hydroxymethyl, hydroxyethyl, cyclopropyl, 3-oxacyclopentanyl, 3-oxetanyl, or 1, 1-dioxothietanyl, which can be optionally further mono-or independently multi-substituted by R 4 ; and each R 4 is independently selected from: hydroxyl, fluoro, chlor
  • ring A is 4-pyridinyl, 4-pyridazinyl, 5-pyridinyl-2-one, imidazo [1, 2-a] pyridin-6-yl, [1, 2, 4] triazolo [4, 3-a] pyridin-6-yl, 6-benzimidazolyl, 6-benzthiazolyl, quinolin-6-yl, or quinoxalin-6-yl; m is 0, 1 or 2; and each R 1 is independently selected from fluoro, chloro, cyano, amino, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxyl, difluoromethoxyl, methylamino, dimethylamino, hydroxyethyl, cyclopropyl, oxacyclopentanyl, 3-oxetanyl, or 1, 1-dioxothietanyl.
  • ring Q is 5-6 membered saturated or unsaturated carbocyclyl, or 5-6 membered saturated or unsaturated heterocyclyl selected from:
  • ring Q is pyrrolidyl, phenyl, or pyridinyl.
  • each R 3 is independently selected from halogen, cyano, amino, C 1-12 alkyl, C 1-12 alkoxyl, C 1-12 haloalkoxyl, N, N- (C 1-12 alkyl) 2 amino, or C 1-12 alkanoylamino.
  • each R 3 is independently selected from fluoro, chloro, cyano, amino, methyl, ethyl, n-propyl, isopropyl, methoxyl, fluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxyl, methylamino, dimethylamino, isopropylamino, ethoxyl, trifluoroethoxy, or ethylamino.
  • each R 3 is independently selected from: amino, cyano, methyl, fluoro, chloro, difluoromethoxyl, methoxyl, or dimethylamino.
  • i 0.
  • i 1
  • i is 2.
  • i 3.
  • i 4.
  • i 0, 1 or 2.
  • ring B is selected from:
  • ring B is selected from 1-azetidinyl, 2-oxa-6-aza-spiro [3.4] octan-5-yl, 1-pyrrolidyl, 1-piperazinyl, 2-oxazolyl, 2-thiazolyl, 1-pyrazolyl, 4-pyrazolyl, 1- [1, 2, 3] triazolyl, 1- [1, 2, 5] triazolyl, phenyl, 2-pyridinyl, 3-pyridinyl, 4-morpholinyl, or 5-indolyl.
  • each R 2 is independently selected from fluoro, chloro, cyano, methyl, amino, ethyl, methoxyl, fluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxyl, trifluoromethoxyl, ethoxyl, methylamino, dimethylamino, ethylamino, isopropanylamino, hydromethyl, or hydroxyethyl.
  • each R 2 is independently selected from cyano, chloro, fluoro, methyl, methoxyl, difluoromethyl, trifluoromethyl, or dimethylamino.
  • n 0.
  • n 1
  • n is 2.
  • n 3.
  • n 4.
  • n 0, 1 or 2.
  • n 0, 1, or 2; and each R 2 is independently selected from cyano, chloro, fluoro, methyl, methoxyl, difluoromethyl, trifluoromethyl, or dimethylamino.
  • ring B is selected from 1-azetidinyl, 2-oxa-6-aza-spiro [3.4] octan-5-yl, 1-pyrrolidyl, 1-piperazinyl, 2-oxazolyl, 2-thiazolyl, 1-pyrazolyl, 4-pyrazolyl, 1- [1, 2, 3] triazolyl, 1- [1, 2, 5] triazolyl, phenyl, 2-pyridinyl, 3-pyridinyl, 4-morpholinyl, or 5-indolyl; n is 0, 1, or 2; and each R 2 is independently selected from cyano, chloro, fluoro, methyl, methoxyl, difluoromethyl, trifluoromethyl, or dimethylamino.
  • R 1 is selected from hydroxyl, cyano, amino, C 1-12 alkyl, C 1-12 haloalkyl, C 1-12 alkoxyl, C 1-12 haloalkoxyl, C 1-12 alkyl-OH, N- (C 1-12 alkyl) amino, N, N- (C 1-12 alkyl) 2 amino, a 3-10 membered saturated or unsaturated carbocyclyl, or a 3-10 membered saturated or unsaturated heterocyclyl, which can be optionally mono-or independently multi-substituted by R 4 ;
  • each R 2 is independently selected from halogen, hydroxyl, cyano, amino, C 1-12 alkyl, C 1-12 haloalkyl, C 1-12 alkoxyl, C 1-12 haloalkoxyl, C 1-12 alkyl-OH, N- (C 1-12 alkyl) amino, or N, N- (C 1-12 alkyl) 2 amino;
  • each R 3 is independently selected from halogen, hydroxyl, cyano, amino, C 1-12 alkyl, C 1-12 haloalkyl, C 1-12 alkoxyl, C 1-12 haloalkoxyl, C 1-12 alkyl-OH, N- (C 1-12 alkyl) amino, or N, N- (C 1-12 alkyl) 2 amino;
  • each R 4 is independently selected from halogen, hydroxyl, cyano, amino, C 1-12 alkyl, C 1-12 haloalkyl, C 1-12 alkoxyl, C 1-12 haloalkoxyl, C 1-12 alkyl-OH, N- (C 1-12 alkyl) amino, N, N- (C 1-12 alkyl) 2 amino, or C 1-12 alkanoylamino; ,
  • W is bond, O, S, -NH-, C 1-12 alkylene, or C 1-12 alkylene-NH-,
  • n 0, 1, 2, 3 or 4;
  • i 0, 1, 2, 3 or 4.
  • R 1 is C 1-12 alkyl.
  • R 1 is methyl
  • R 1 is isopropyl
  • n 1
  • R 2 is halogen
  • R 2 is fluoro
  • R 3 is halogen
  • R 3 is fluoro
  • W is methylene
  • the present disclosure provides a compound of Formula (I) selected from:
  • linking substituents are described. Where the structure clearly requires a linking group, the Markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the Markush group definition for that variable lists “alkyl” , then it is understood that the “alkyl” represents a linking alkylene group.
  • substituted when refers to a chemical group, means the chemical group has one or more hydrogen atoms that is/are removed and replaced by substituents.
  • substituted has the ordinary meaning known in the art and refers to a chemical moiety that is covalently attached to, or if appropriate, fused to, a parent group.
  • optionally substituted or optionalally...substituted means that the chemical group may have no substituents (i.e. unsubstituted) or may have one or more substituents (i.e. substituted) . It is to be understood that substitution at a given atom is limited by valency.
  • C i-j indicates a range of the carbon atoms numbers, wherein i and j are integers and the range of the carbon atoms numbers includes the endpoints (i.e. i and j) and each integer point in between, and wherein j is greater than i.
  • C 1-6 indicates a range of one to six carbon atoms, including one carbon atom, two carbon atoms, three carbon atoms, four carbon atoms, five carbon atoms and six carbon atoms.
  • the term “C 1-12 ” indicates 1 to 12, including 1 to 10, 1 to 8, 1 to 6, 1 to 5, 1 to 4, 1 to 3 or 1 to 2 carbon atoms.
  • alkyl refers to a saturated or unsaturated hydrocarbon chain, while the latter may be further subdivided into hydrocarbon chain having at least one double or triple bonds (alkenyl or alkynyl) .
  • alkyl refers to a saturated hydrocarbon chain.
  • the hydrocarbon chain mentioned above may be straight-chain or branched-chain.
  • C i-j alkyl refers to an alkyl having i to j carbon atoms.
  • saturated alkyl group examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; higher homologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1, 2, 2-trimethylpropyl, and the like.
  • Examples of unsaturated alkyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, ethynyl, propyn-1-yl, propyn-2-yl, and the like.
  • Examples of “C 1-12 alkyl” are methyl, ethyl, propyl, isopropyl and butyl.
  • Examples of “C 1-3 alkyl” are methyl, ethyl, propyl and isopropyl.
  • alkylene refers to a divalent alkyl.
  • alkylene groups include, but are not limited to, methylene, 1, 1-ethylene, 1, 2-ethylene, 1, 1-propylene, 1, 2-propylene, 1, 3-propylene, 2, 2-propylene, and the like.
  • halo and “halogen” refer to an atom selected from fluorine, chlorine, bromine or iodine.
  • alkoxy refers to a group of formula -O-alkyl.
  • C i-j alkoxy means that the alkyl moiety of the alkoxy group has i to j carbon atoms.
  • alkoxy groups include, but are not limited to, methoxyl, ethoxyl, propoxyl (e.g. n-propoxy and isopropoxy) , t-butoxy, and the like.
  • Examples of “C 1-12 alkoxyl” are methoxyl, ethoxyl and propoxyl.
  • C i-j alky-OH refers to a group of formula “-C 1-12 alkyl-OH” , wherein the alkyl moiety of the group has i to j carbon atoms, and one or more hydroxyl groups may be linked to any carbon atoms in the alkyl moiety.
  • “C i-j alky-OH” has one hydroxyl group.
  • Examples of “C 1-12 alkyl-OH” are hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl and 1-hydroxyisopropyl.
  • C i-j haloalkyl refers to a halogen substituted (mono-or multi-substituted) C i-j alkyl group.
  • C 1-12 haloalkyl are fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, chloroethyl and bromoisopropyl.
  • difluoroethyl are 1, 1-difluoroethyl.
  • trifluoroethyl are 2, 2, 2-trifluoroethyl and 1, 2, 2-trifluoroethlyl.
  • C i-j haloalkoxyl are fluoromethoxyl, difluoromethoxyl, or trifluoromethoxyl.
  • trifluoroethoxy are 2, 2, 2-trifluoroethoxy and 1, 2, 2-trifluoroethoxy.
  • N- (C 1-12 alkyl) amino are methylamino and ethylamino.
  • N- (C 1-12 haloalkyl) amino are fluoromethylamino, difluoromethylamino, trifluoromethylamino, 2-chloroethylamino and 1-bromoisopropylamino.
  • C i-j alkanoyl refers to C i-j alkylcarbonyl.
  • Examples of “C 1-12 alkanoyl” are propionyl and acetyl.
  • C 1-12 alkanoylamino are formamido, acetamido and propionylamino.
  • C 1-12 alkanoyloxy are acetoxy.
  • C 1-12 alkoxycarbonyl are methoxycarbonyl, ethoxycarbonyl, n-and t-butoxycarbonyl
  • carbamoyl refers to aminocarbonyl group.
  • N- (C 1-12 alkyl) carbamoyl are methylaminocarbonyl and ethylaminocarbonyl.
  • N, N- (C 1-12 alkyl) 2 carbamoyl are dimethylaminocarbonyl and methylethylaminocarbonyl.
  • N, N- (C 1-12 alkyl) 2 amino are di- (N-methyl) amino, di- (N-ethyl) amino and N-ethyl-N-methylamino.
  • the term “carbocyclyl” refers to any ring, including mono-or poly-cyclic ring (s) (e.g. having 2 or 3 fused, bridged or spiro rings) , in which all the ring atoms are carbon and which contains at least three ring forming carbon atoms.
  • the carbocyclyl may contain 3 to 12 ring forming carbon atoms (i.e. 3-12 membered carbon atoms) , 3 to 10 ring forming carbon atoms, 3 to 9 ring forming carbon atoms or 4 to 8 ring forming carbon atoms.
  • Carbocyclyl groups may be saturated, partially unsaturated or fully unsaturated.
  • the carbocyclyl group may be a saturated cyclic alkyl group.
  • the carbocyclyl group may be an unsaturated cyclic alkyl group that contains at least one double bond in its ring system.
  • an unsaturated carbocyclyl group may contains one or more aromatic rings.
  • one or more ring forming -CH 2 -group of the saturated or unsaturated carbocyclyl may be replaced by a -C (O) -group.
  • the carbocyclyl group is a monocyclic alkyl group. In some embodiments, the carbocyclyl group is a saturated monocyclic alkyl group. Examples of monocyclic saturated or unsaturated carbocyclyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, and the like.
  • spiro rings refers to ring systems having two rings connected through one single common atom; the term “fused” rings refers to ring systems having two rings sharing two adjacent atoms; and the term “bridged” rings refers to ring systems with two rings sharing three or more atoms.
  • a 3-12, 3-10 or 5-6 “membered saturated or unsaturated carbocyclyl” is a saturated, partially unsaturated or fully unsaturated mono-or poly-cyclic ring system having 3 to 12, 3 to 10, or 5 to 6 ring forming carbon atoms respectively, wherein one or more ring forming -CH 2 -group can optionally be replaced by a -C (O) -group.
  • Examples of “3-12 membered saturated or unsaturated carbocyclyl” are C 3-4 cycloalkyl, cyclohexyl, cyclohexenyl, cyclopentyl, phenyl, naphthyl and bicyclo [1.1.1] pentan-1-yl.
  • Examples of “C 3-4 cycloalkyl” are cyclopropyl and cyclobutyl.
  • Examples of “5-6 membered saturated or unsaturated carbocyclyl” are cyclopentyl and phenyl.
  • heterocyclyl refers to a carbocyclyl group, wherein one or more (e.g. 1, 2 or 3) ring atoms are replaced by heteroatoms, which include, but are not limited to, O, S, N, P, and the like.
  • the heterocyclyl is a saturated heterocyclyl.
  • the heterocyclyl is an unsaturated heterocyclyl having one or more double bonds in its ring system.
  • the heterocyclyl is a partially unsaturated heterocyclyl.
  • the heterocyclyl is a fully unsaturated heterocyclyl.
  • an unsaturated heterocyclyl group may contain one or more aromatic rings.
  • one or more ring forming -CH 2 -group of the heterocyclyl can optionally be replaced by a -C (O) -, a -S-, a -S (O) -, or a -S (O) 2 -group.
  • said ring forming sulphur atom may be optionally oxidised to form the S-oxides.
  • the heterocyclyl is linked to the other portion of a compound through its ring forming carbon.
  • the heterocyclyl is linked to the other portion of a compound through its ring forming nitrogen.
  • a 3-12, 3-10 or 5-6 “membered saturated or unsaturated heterocyclyl” is a saturated, partially unsaturated or fully unsaturated mono-or poly-cyclic ring (s) (e.g. having 2 or 3 fused, bridged or spiro rings) system having 3 to 12, 3 to 10, or 5 to 6 ring forming atoms respectively, of which at least one ring forming atom is chosen from nitrogen, sulphur or oxygen, which may, unless otherwise specified, linked to the other portion of a compound through its ring forming carbon or nitrogen, wherein one or more ring forming -CH 2 -group of the saturated or unsaturated heterocyclyl may be replaced by a -C (O) -, a -S-, a -S (O) -, or a -S (O) 2 -group, and wherein when the heterocyclyl contains a sulphur in its ring system, said ring sulphur atom may be optionally oxidised to
  • Exemplary monocyclic heterocyclyl groups include, but are not limited to oxetanyl, 1, 1-dioxothietanylpyrrolidyl, tetrahydrofuryl, tetrahydrothienyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, piperidyl, piperidyl, piperazinyl, morpholinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, pyridonyl, pyrimidonyl, pyrazinonyl, pyrimidonyl, pyridazonyl, triazinonyl, and the like.
  • spiro heterocyclyl examples include, but are not limited to, spiropyranyl, spirooxazinyl, and the like.
  • fused heterocyclyl examples include, but are not limited to, phenyl fused ring or pyridinyl fused ring, such as quinolinyl, isoquinolinyl, quinoxalinyl, quinolizinyl, quinazolinyl, azaindolizinyl, pteridinyl, chromenyl, isochromenyl, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, benzofuranyl, isobenzofuranyl, benzimidazolyl, benzothienyl, benzothiazolyl, carbazolyl, phenazinyl, phenothiazinyl, phenanthridinyl, imidazo [1, 2-a] pyridin
  • bridged heterocyclyl examples include, but are not limited to, morphanyl, hexamethylenetetraminyl, 8-aza-bicyclo [3.2.1] octane, 1-aza-bicyclo [2.2.2] octane, 1, 4-diazabicyclo [2.2.2] octane (DABCO) , and the like.
  • stereoisomer refers to any of the various stereoisomeric configurations (e.g. enantiomers, diastereomers and racemates) of an asymmetric compound (e.g. those having one or more asymmetrically substituted carbon atoms or “asymmetric centers” ) .
  • asymmetric compound e.g. those having one or more asymmetrically substituted carbon atoms or “asymmetric centers”
  • Compounds of the present disclosure that contain asymmetric centers can be isolated in optically active (enantiomers or diastereomers) or optically inactive (racemic) forms.
  • enantiomer includes pairs of stereoisomers that are non-superimposable mirror images of each other.
  • a 1: 1 mixture of a pair of enantiomers is a “racemic mixture” .
  • diastereomers or “diastereoisomers” include stereoisomers that have at least two asymmetric atoms, but which are not mirror images of each other. Certain compounds containing one or more asymmetric centers may give rise to enantiomers, diastereomers or other stereoisomeric forms that may be defined, in terms of absolute configuration, as (R) -or (S) -at each asymmetric center according to the Cahn-Ingold-Prelog R-S system. Resolved compounds whose absolute configuration is unknown can be designated using the term “or” at the asymmetric center. Methods on how to prepare optically active forms from racemic mixtures are known in the art, such as resolution by HPLC or stereoselective synthesis.
  • geometric isomers or “cis and trans isomers” refer to compounds with same formula but their functional groups are rotated into a different orientation in three-dimensional space.
  • tautomers include prototropic tautomers that are isomeric protonation states of compounds having the same formula and total charge.
  • prototropic tautomers include, but are not limited to, ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, enamine-imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H-and 3H-imidazole, 1H-, 2H-and 4H-1, 2, 4-triazole, 1H-and 2H-isoindole, and 1H-and 2H-pyrazole.
  • Tautomers can be in equilibrium or sterically locked into one form by appropriate substitution.
  • Compounds of the present disclosure identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.
  • the “compound” of the present disclosure is also intended to encompass all isotopes of atoms in the compounds.
  • Isotopes of an atom include atoms having the same atomic number but different mass numbers.
  • hydrogen, carbon, nitrogen, oxygen, phosphorous, sulphur, fluorine, chlorine, bromide or iodine in the “compound” of present disclosure are meant to also include their isotopes such as but are not limited to: 1 H, 2 H, 3 H, 11 C, 12 C, 13 C, 14 C, 14 N, 15 N, 16 O, 17 O, 18 O, 31 P, 32 P, 32 S, 33 S, 34 S, 36 S, 17 F, 19 F, 35 Cl, 37 Cl, 79 Br, 81 Br, 127 I and 131 I.
  • hydrogen includes protium, deuterium and tritium.
  • carbon includes 12 C and 13 C.
  • “compound” of the present disclosure only encompasses the isotopes of hydrogen in the compound. In some embodiments, “compound” of the present disclosure only encompasses the isotopes of atoms in natural abundance.
  • the term “pharmaceutically acceptable” refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • compounds, materials, compositions, and/or dosage forms that are pharmaceutically acceptable refer to those approved by a regulatory agency (such as U.S. Food and Drug Administration, China Food and Drug Administration or European Medicines Agency) or listed in generally recognized pharmacopoeia (such as U.S. Pharmacopoeia, China Pharmacopoeia or European Pharmacopoeia) for use in animals, and more particularly in humans.
  • “pharmaceutically acceptable salts” refers to derivatives of the compounds of present disclosure wherein the parent compound is modified by converting an existing acidic moiety (e.g. carboxyl and the like) or base moiety (e.g. amine, alkali and the like) to its salt form.
  • compounds of present disclosure are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
  • the pharmaceutically acceptable salts are acid and/or base salts that retain biological effectiveness and properties of the parent compound, which typically are not biologically or otherwise undesirable.
  • Suitable pharmaceutically acceptable salts of a compound of the present disclosure includes, for example, an acid-addition salt, which can be derived from for example an inorganic acid (for example, hydrochloric, hydrobromic, sulfuric, nitric, phosphoric acid and the like) or organic acid (for example, formic, acetic, propionic, glycolic, oxalic, maleic, malonic, succinic, fumaric, tartaric, trimesic, citric, lactic, phenylacetic, benzoic, mandelic, methanesulfonic, napadisylic, ethanesulfonic, toluenesulfonic, trifluoroacetic, salicylic, sulfosalicylic acids and the like) .
  • the pharmaceutically acceptable salt of the compound of the present disclosure is a formic acid salt.
  • the pharmaceutically acceptable salt of the compound of the present disclosure is a TFA salt.
  • Suitable pharmaceutically acceptable salts of a compound of the present disclosure also include, for example, an base-addition salt, which can be derived from for example an inorganic bases (for example, sodium, potassium, ammonium salts and hydroxide, carbonate, bicarbonate salts of metals from columns I to XII of the periodic table such as calcium, magnesium, iron, silver, zinc, copper and the like) or organic bases (for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like) .
  • an inorganic bases for example, sodium, potassium, ammonium salts and hydroxide, carbonate, bicarbonate salts of metals from columns I to XII of the periodic table such as calcium, magnesium, iron, silver, zinc, copper and the like
  • organic bases for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines,
  • organic amines include but are not limited to isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.
  • acids or bases for forming acid/base-addition salts other than those shown in the examples may also be possible. Lists of additional suitable salts can be found, e.g. in “Remington's Pharmaceutical Sciences” , 20th ed., Mack Publishing Company, Easton, Pa., (1985) ; and in “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) .
  • Suitable pharmaceutically acceptable salts of a compound of the present disclosure is inorganic bases salt.
  • the present disclosure also includes active intermediates, active metabolites and prodrugs of the compounds of present disclosure.
  • an “active intermediate” refer to intermediate compound in the synthetic process, which exhibits the same or essentially the same biological activity as the final synthesized compound.
  • an “active metabolite” refers to a break-down or end product of a compound of the present disclosure or its salt or prodrug produced through metabolism or biotransformation in the animal or human body, which exhibits the same or essentially the same biological activity as the specified compound. Such metabolites may result from, for example, oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, and the like, of the administered compound or salt or prodrug.
  • prodrugs refer to any compounds or conjugates which release the active parent drug when administered to an animal or human subject.
  • Prodrugs can be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleavable, either in routine manipulation or in vivo, from the parent compounds.
  • Prodrugs include compounds wherein hydroxyl, amino, sulfhydryl, or carboxyl group is bonded to any group that, when administered to a mammalian subject, is cleavable to form a free hydroxyl, amino, sulfhydryl, or carboxyl group respectively.
  • prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the present disclosure. Preparation and use of prodrugs is discussed in T. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems” , Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are hereby incorporated by reference in their entirety.
  • Synthesis of the compounds provided herein, including pharmaceutically acceptable salts thereof, are illustrated in the synthetic schemes in the examples.
  • the compounds provided herein can be prepared using any known organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes, and thus these schemes are illustrative only and are not meant to limit other possible methods that can be used to prepare the compounds provided herein. Additionally, the steps in the Schemes are for better illustration and can be changed as appropriate.
  • the embodiments of the compounds in examples were synthesized for the purposes of research and potentially submission to regulatory agencies.
  • the reactions for preparing compounds of the present disclosure can be carried out in suitable solvents, which can be readily selected by one skilled in the art of organic synthesis.
  • suitable solvents can be substantially non-reactive with the starting materials (reactants) , the intermediates, or products at the temperatures at which the reactions are carried out, e.g. temperatures that can range from the solvent's freezing temperature to the solvent's boiling temperature.
  • a given reaction can be carried out in one solvent or a mixture of more than one solvent.
  • suitable solvents for a particular reaction step can be selected by one skilled in the art.
  • Preparation of compounds of the present disclosure can involve the protection and deprotection of various chemical groups.
  • the need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art.
  • the chemistry of protecting groups can be found, for example, in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd Ed., Wiley & Sons, Inc., New York (1999) , which is incorporated herein by reference in its entirety.
  • Reactions can be monitored according to any suitable method known in the art.
  • product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g. 1 H or 13 C) , infrared spectroscopy, spectrophotometry (e.g. UV-visible) , mass spectrometry, or by chromatographic methods such as high performance liquid chromatography (HPLC) , liquid chromatography-mass spectroscopy (LCMS) , or thin layer chromatography (TLC) .
  • HPLC high performance liquid chromatography
  • LCMS liquid chromatography-mass spectroscopy
  • TLC thin layer chromatography
  • Compounds can be purified by one skilled in the art by a variety of methods, including high performance liquid chromatography (HPLC) ( “Preparative LC-MS Purification: Improved Compound Specific Method Optimization” Karl F. Blom, Brian Glass, Richard Sparks, Andrew P. Combs J. Combi. Chem. 2004, 6 (6) ,
  • the structures of the compounds in the examples are characterized by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS) .
  • NMR chemical shift ( ⁇ ) is given in the unit of 10 -6 (ppm) .
  • 1 H-NMR spectra is recorded in dimethyl sulfoxide-d6 (DMSO-d6) or CDCl3 or CD3OD or D2O or Acetone_d 6 or CD 3 CN (from Innochem or Sigma-Aldrich or Cambridge Isotope Lab., Inc. ) on Bruker AVANCE NMR (300 MHz or 400 MHz) spectrometers using ICON-NMR (under TopSpin program control) with tetramethylsilane as an internal standard.
  • DMSO-d6 dimethyl sulfoxide-d6
  • CDCl3 or CD3OD or D2O or Acetone_d 6 or CD 3 CN
  • MS measurement is carried out using Shimadzu 2020 Mass Spectrometer with an electrospray source at positive and negative ion mode.
  • High Performance Liquid Chromatography (HPLC) measurement is carried out on Shimadzu LC-20AD systems or Shimadzu LC-20ADXR systems or Shimadzu LC-30AD systems using Shim-pack XR-ODS C18 column (3.0*50 mm, 2.2 ⁇ m) , or Ascentis Express C18 column (2.1*50 mm, 2.7 ⁇ m) , or Agilent Poroshell HPH-C18 column (3.0*50 mm, 2.7 ⁇ m) .
  • Thin layer chromatography is carried out using Sinopharm Chemical Reagent Beijing Co., Ltd. and Xinnuo Chemical silica gel plates.
  • the silica gel plates used for thin layer chromatography (TLC) are 175 -225 ⁇ m.
  • the silica gel plates used for separating and purifying products by TLC are 1.0 mm.
  • Purified chromatographic column uses the silica gel as the carrier (100 ⁇ 200, 200 ⁇ 300 or 300 ⁇ 400 mesh, produced by Rushanshi Shangbang Xincailiao Co., Ltd. or Rushan Taiyang Desiccant Co., Ltd. etc. ) , or flash column (reversed phase C18 column 20-45 ⁇ m, produced by Agela Technologies) in Agela Technologies flash system. The size of columns are adjusted according to the amount of compounds.
  • the known starting materials of the present disclosure can be synthesized by using or according to the known methods in the art, or can be purchased from Alfa Aesar, TCI, Sigma-Aldrich, Bepharm, Bide pharmatech, PharmaBlock, Enamine, Innochem and JW&Y PharmLab etc.
  • the reactions are all carried out under argon or nitrogen atmosphere.
  • Argon or nitrogen atmosphere refers to that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1 L. Hydrogenation is usually carried out under pressure.
  • the reaction temperature in the examples is ambient temperature, which is 10°C ⁇ 30°C.
  • the reaction progress are monitored by TLC or/and LC-MS.
  • the eluent systems used for the reactions include dichloromethane-methanol system and petroleum ether-ethyl acetate system.
  • the volume ratios of the solvents are adjusted according to the different polarities of compounds.
  • the elution system of column chromatography used for purifying compounds and eluent system of TLC include dichloromethane-methanol system and petroleum ether-ethyl acetate system.
  • the volume ratios of the solvents are adjusted according to the different polarities of compounds.
  • a small amount of alkaline or acidic agents (0.1% ⁇ 1%) such as formic acid, or acetic acid, or TFA, or ammonia can be added for adjustment.
  • the present disclosure provides pharmaceutical compositions comprising at least one compound of the present disclosure, or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition comprises more than one compound of the present disclosure, or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition comprises one or more compounds of the present disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutical acceptable carrier.
  • the pharmaceutically acceptable carriers are conventional medicinal carriers in the art which can be prepared in a manner well known in the pharmaceutical art.
  • the compounds of the present disclosure, or a pharmaceutically acceptable salt thereof may be admixed with pharmaceutically acceptable carrier for the preparation of pharmaceutical composition.
  • the form of pharmaceutical compositions depends on a number of criteria, including, but not limited to, route of administration, extent of disease, or dose to be administered.
  • the pharmaceutical compositions can be formulated for oral, nasal, rectal, percutaneous, intravenous, or intramuscular administration.
  • the pharmaceutical compositions can be formulated in the form of tablets, capsule, pill, powder, granule, sachets, cachets, lozenges, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium) , spray, ointment, paste, cream, lotion, gel, patch, inhalant, or suppository.
  • the pharmaceutical compositions comprise about 1 mg to about 1000 mg of the compounds of the present disclosure, or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical compositions comprise one or more compounds of the present disclosure, or a pharmaceutically acceptable salt thereof, as a first active ingredient, and further comprise a second active ingredient.
  • the second active ingredient can be any immunomodulator or anti-tumour agent known in the art, including without limitation, chemotherapeutics, immunotherapeutics, cell signal transduction inhibitors, cell signal transduction inhibitors, alkylating agents, topoisomerase inhibitors, mitosis inhibitors, antihormonal agents, etc.
  • immunomodulators or anti-tumour agents are, platinum based chemotherapeutics (e.g., Cisplatin (DDP) , Carboplatin (CBP) , Sulfato-1, 2-diaminocyclohexane platinum (SHP) , Nedaplatin, Oxaliplatin (OXA) , Laboplatin) , Docetaxel, Paclitaxel, Doxorubicin, Etoposide, Mitoxantrone, CTLA-4 inhibitors, anti-CTLA-4 antibodies, PD-1 inhibitors, PD-L1 inhibitors, anti-PD-1/PD-L1 antibodies, CD39 inhibitors, anti-CD39 antibodies, CD73 inhibitors, anti-CD73 antibodies, CCR2 inhibitors, anti-CCR2 antibodies, EGFR inhibitors, CDK 4/6 inhibitors, MELK inhibitors, OX40 agonists, antiandrogen inhibitors, IgG4 isotype antibodies, tyrosine kinase inhibitors,
  • anti tumour agents for treating cancers or tumors may include, but are not limited to, cisplatin, carboplatin, SHP, nedaplatin, oxaliplatin, laboplatin, docetaxel, paclitaxel, doxorubicin, etoposide, mitoxantrone, vincristine, vinblastine, gemcitabine, cyclophosphamide, chlormabucil, carmustine, methotrexate, fluorouracil, actinomycin, epirubicin, anthracycline, bleomycin, mitomycin-C, irinotecan, topotecan, teniposide interleukin, interferon, tremelimumab, ipilimumab, pembrolizumab, nivolumab, avelumab, durvalumab, atezolizumab, IPH 52, IPH 53, CPI-006, plozaliz
  • Adenosine receptor-associated diseases defined hereinafter may be applied as a sole therapy or may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy or immunotherapy.
  • chemotherapy may include one or more of the following chemotherapeutics: Cisplatin (DDP) , Carboplatin (CBP) , Sulfato-1, 2-diaminocyclohexane platinum (SHP) , Nedaplatin, Oxaliplatin (OXA) , Laboplatin, Docetaxel, Paclitaxel, Doxorubicin, Etoposide, or Mitoxantrone.
  • Such immunotherapeutics may include one or more of the following anti-tumour agents: (i) an anti-CTLA-4 antibody; (ii) an anti-PD-1 antibody; (iii) an anti-PD-L1 antibody; (iv) an anti-CD73 antibody; (v) an anti-CD39 antibody; or (vi) an anti-CCR2 antibody.
  • an anti-CTLA-4 antibody is tremelimumab (as disclosed in US 6,682,736) .
  • an anti-CTLA-4 antibody is ipilimumab (marketed by Bristol Myers Squib as ) .
  • an anti-PD-L1 antibody is an antibody as disclosed in US 20130034559 (MedImmune) .
  • an anti-PD-L1 antibody is an antibody as disclosed US 2010/0203056 (Genentech/Roche) .
  • an anti-PD-L1 antibody is an antibody as disclosed US 20090055944 (Medarex) .
  • an anti-PD-L1 antibody is an antibody as disclosed US 20130323249 (Sorrento Therapeutics) .
  • an anti-PD-1 antibody is MRK-3475 (Merck) .
  • an anti-PD-1 antibody is Nivolumab, or an anti-PD-1 antibody as disclosed in WO 2006/121168 or US 8,008,449 (Medarex) .
  • an anti-PD-1 antibody is an antibody as disclosed in WO2009/101611 (CureTech) .
  • particularly an anti-PD-1 antibody is an antibody as disclosed in WO2012/145493 (Amplimmune) .
  • particularly an anti-PD-1 antibody is an antibody as disclosed in US 7,488,802 (Wyeth/MedImmune) .
  • an anti-PD-1 antibody is an antibody as disclosed in US 20130280275 (Board of Regents, Univ. of Texas) .
  • particularly an anti-PD-1 antibody is an antibody as disclosed in WO 99/42585 (Agonox) , WO 95/12673 and WO 95/21915.
  • an anti-CD39 antibody is IPH52 (Innate Pharmaceuticals) .
  • an anti-CD73 antibody is CPI-006 (Corvus Pharmaceuticals) or IPH53 (Innate Pharmaceuticals) .
  • an anti-CCR2 antibody is plozalizumab (Takeda Pharmaceuticals International Co. ) or MLN1202 (Millennium Pharmaceuticals) .
  • a combination suitable for use in the treatment of an Adenosine receptor-associated disease, especially cancer comprising a compound of formula (I) as defined hereinbefore or a pharmaceutically acceptable salt thereof and any one or more of the chemotherapeutics listed above and/or any one or more of the immonotherapeutics listed under (i) – (vi) above.
  • the compounds of present disclosure may be provided in combination with an anti-PD1/PD-L1 antibody.
  • the compounds of present disclosre may be provided in combination with an an anti-PD1/PD-L1 antibody and further in combination of an anti-CTLA-4, CD38, CD73, or CCR2 antibody.
  • a combination suitable for use in the treatment of cancer comprising a compound of formula (I) as defined hereinbefore or a pharmaceutically acceptable salt thereof and any one of the immunomodulators or anti tumour agents listed above.
  • “combination” refers to simultaneous, separate or sequential administration. In some embodiments, “combination” refers to simultaneous administration. In another aspect of the present disclosure, “combination” refers to separate administration. In a further aspect of the present disclosure, “combination” refers to sequential administration. Where the administration is sequential or separate, the delay in administering the second component should not be such as to lose the beneficial effect of the combination.
  • a pharmaceutical composition which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with an immunomodulator or anti-tumour agent selected from those listed above, in association with a pharmaceutically acceptable diluent or carrier.
  • a pharmaceutical composition which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with an immunomodulator or anti-tumour agent selected from one listed above, in association with a pharmaceutically acceptable diluent or carrier for use in producing an immunomodulating or anti-cancer effect.
  • a pharmaceutical composition which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with an immunomodulator or anti-tumour agent selected from one listed above, in association with a pharmaceutically acceptable diluent or carrier for use in treating NSCLC, RCC, prostate cancer, or breast cancer (etc. ) .
  • kits comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with an immunomodulator or anti-tumour agent selected from one listed above.
  • a kit comprising:
  • the compounds of formula (I) are also useful as pharmacological tools in the development and standardisation of in vitro and in vivo test systems for the evaluation of the activity or the expression of adenosine receptors in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents.
  • the present disclosure provides a method of treating a disease associated with adenosine receptors (including, for example, A1, A2a, and/or A2b, particularly A2a) by administering to a subject a therapeutically effective amount of one or more compounds, pharmaceutically acceptable salts thereof or the pharmaceutical composition of the present disclosure.
  • adenosine receptors including, for example, A1, A2a, and/or A2b, particularly A2a
  • the term “disease associated with adenosine receptors ” or “AR associated disease” refers to a disease whose onset or development or both is associated with the genomic alterations, expression, over-expression, degradation or activity of AR (including, for example, A1, A2a, and/or A2b, especially A2a) , as the case may be. Examples include but are not limited to, inflammatory disorders, cancer, Parkinson disease, epilepsy, cerebral ischemia and stroke, sepression, cognitive impairment, HIV, ADA-SCID, acute heart failure (AHF) and chronic heart failure, chronic obstructive pulmonary disease (COPD) , asthma, and other diseases.
  • AR associated disease refers to a disease that will be treated by inhibition of the effect of Adenosine receptor.
  • the AR associated disease is cancer, preferably an AR-expressing cancer, or AR-overexpressing cancer.
  • An “AR-expressing cancer” is one that involves cancer cells or tumor cells having AR protein, such as A2a, A1 and/or A2b, present at their cell surface.
  • An “AR-overexpressing cancer” is one which has significantly higher levels of AR protein, such as A2a, A1 and/or A2b, at the cell surface of a cancer or tumor cell, compared to a noncancerous cell of the same tissue type. Such overexpression may be caused by gene amplification or by increased transcription or translation.
  • Adenosine receptor expression or overexpression may be determined in a diagnostic or prognostic assay by evaluating increased levels of the AR proteins present on the surface of a cell (e.g. via an immunohistochemistry assay; IHC) .
  • IHC immunohistochemistry assay
  • one may measure levels of AR-encoding nucleic acid in the cell e.g. via fluorescent in situ hybridization (FISH; see WO98/45479 published October, 1998) , southern blotting, or polymerase chain reaction (PCR) techniques, such as real time quantitative PCR (RT-PCR) (Methods 132: 73-80 (1990) ) .
  • FISH fluorescent in situ hybridization
  • PCR polymerase chain reaction
  • RT-PCR real time quantitative PCR
  • a detectable label e.g. a radioactive isotope
  • the cancers include but are not limited to, lung cancer (e.g. non-small cell lung cancer (NSCLC) , small cell lung cancer, lung adenocarcinoma, large cell lung cancer, squamous cell lung cancer) , renal cell carcinoma (RCC) , prostate cancer, breast cancer, ovarian cancer, endometrial cancer, cervical cancer, bone cacner, uterine cancer, colon cancer, leukemia, glioblastoma, melanoma, chondrosarcoma, brain cancer, cholangiocarcinoma, osteosarcoma, lymphoma, adenoma, myeloma, hepatocellular carcinoma, adrenocortical carcinoma, pancreatic cancer, bladder cancer, liver cancer, gastric cancer, colorectal cancer, esophageal cancer, testicular cancer, skin cancer, kidney cancers, mesothelioma, neuroblastoma, thyroid cancer, head and neck cancers, esophage
  • the cancer is NSCLC, RCC, prostate cancer, or breast cancer.
  • the cancer as mentioned herein can be at any stage, unless otherwise specified.
  • the cancer is early stage cancer.
  • the cancer is locally advanced cancer.
  • the cancer is locally advanced and/or metastatic cancer.
  • the cancer is invasive cancer.
  • the cancer is a cancer resistant to existing therapies.
  • the compounds, or pharmaceutically acceptable salts thereof, of the present disclosure possess potency of treating cancer (e.g., NSCLC, RCC, prostate cancer, breast cancer) .
  • cancer e.g., NSCLC, RCC, prostate cancer, breast cancer
  • the compounds of the present present disclosure, or pharmaceutically acceptable salts thereof may also be useful in the treatment of other Adenosine receptor-associated diseases, for example Parkinson disease, epilepsy, cerebral ischemia and stroke, sepression, cognitive impairment, HIV, ADA-SCID, AHF and chronic heart failure, Chronic obstructive pulmonary disease (COPD) , or Asthma.
  • COPD chronic obstructive pulmonary disease
  • treatment refers to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein.
  • treatment may be conducted after one or more symptoms have developed.
  • treatment may be conducted in the absence of symptoms.
  • treatment may be conducted to a susceptible individual prior to the onset of symptoms (e.g. in light of a history of symptoms and/or in light of genetic or other susceptibility factors) . Treatment may also be continued after symptoms have resolved, for example to present or delay their recurrence.
  • the therapeutically effective amount of a compound or a pharmaceutically acceptable salts thereof as provided herein will depend on various factors known in the art, such as body weight, age, past medical history, present medications, state of health of the subject and potential for cross-reaction, allergies, sensitivities and adverse side-effects, as well as the administration route and extent of disease development. Dosages may be proportionally reduced or increased by one skilled in the art (e.g. physician or veterinarian) as indicated by these and other circumstances or requirements.
  • the present disclosure provides use of the compounds, pharmaceutically acceptable salts thereof, or pharmaceutical composition of the present disclosure in the manufacture of medicaments for the treatment of AR associated diseases.
  • AR associated diseases include but are not limited to cancer (e.g. NSCLC, RCC, prostate, or breast cancer) , and other diseases.
  • the present disclosure also provides a method of screening patient suitable for treating with the compounds or pharmaceutical composition of the present disclosure alone or combined with other ingredients (e.g. a second active ingredient, e.g. anti-tumour agent) .
  • the method includes sequencing the tumor samples from patients and detecting the accumulation or activation of AR.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for modulating adenosine receptors in a warm-blooded animal such as man.
  • modulate refers to an action or result of changing the expression, degradation, and/or activity of the adenosine receptors.
  • a method of modulatingadenosine receptors in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I) , or a pharmaceutically acceptable salt thereof, as defined hereinbefore.
  • a method of treating AR associated diseases in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I) , or a pharmaceutically acceptable salt thereof, as defined hereinbefore.
  • a method for producing an anti-cancer effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I) , or a pharmaceutically acceptable salt thereof, as defined hereinbefore.
  • a method of producing an anti-cancer effect in a warm-blooded animal, such as man, in need of such treatment which comprises (1) determining whether or not the warm blooded animal has an AR-expressing cancer and (2) if so administering to said animal an effective amount of the compound of formula (I) , or a pharmaceutically acceptable salt thereof, as defined hereinbefore.
  • a method of treating NSCLC, RCC, prostate, or breast cancer, in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I) , or a pharmaceutically acceptable salt thereof, as defined hereinbefore.
  • a compound of formula (I) for use in modulating AR in a warm-blooded animal such as man.
  • a compound of formula (I) for use in the treatment of AR associated diseases in a warm-blooded animal such as man.
  • a compound of formula (I) for use in the production of an anti-cancer effect in a warm-blooded animal such as man.
  • a compound of formula (I) for use in the treatment of NSCLC, RCC, prostate, or breast cancer.
  • the compounds of the present disclosure may be prepared by the methods known in the art.
  • the following illustrates the detailed preparation methods of the preferred compounds of the present disclosure. However, they are by no means limiting the preparation methods of the compounds of the present disclosure.
  • Desired product could be detected by LCMS.
  • the crude product (80 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column 30 ⁇ 150 mm 5 ⁇ m; Mobile Phase A: Water (0.05%NH 3 H 2 O) , Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 25%B to 34%B in 7 min; 254/220 nm; Rt: 6.25 min) to afford 5- [5-amino-7- (4-fluorophenyl) -2- [ (3-fluoropyridin-2-yl) methyl] - [1, 2, 4] triazolo [1, 5-c] pyrimi din-8-yl] -1-methyl-1, 2-dihydropyridin-2-one (Cmpd.
  • the residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 /MeOH (10: 1) to afford a crude product.
  • the crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column 19*250 mm, 5 ⁇ m; Mobile Phase A: Water (10 mmol/L NH 4 HCO 3 +0.1 %NH 3 .
  • the residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 /MeOH (10: 1) to afford a crude product.
  • the crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column 30 ⁇ 150 mm 5 ⁇ m; Mobile Phase A: Water (0.05 %NH 3 H 2 O) , Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30%B to 35%B in 7 min; 254/220 nm; Rt: 5.77 min) to afford 7- (4-fluorophenyl) -8- (2-methylpyridin-4-yl) -2- (thiazol-2-ylmethyl) - [1, 2, 4] triazolo [1, 5-c] pyri midin-5-amine (Cmpd.
  • the crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column 30 ⁇ 150 mm 5 ⁇ m; Mobile Phase A: Water (0.05 %NH 3 H 2 O) , Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 40%B to 60%B in 7 min; 254/220 nm; Rt: 6.27 min) to afford 2- [1- (2, 6-difluorophenyl) ethyl] -7- (4-fluorophenyl) -8- (2-methylpyridin-4-yl) - [1, 2, 4] triazolo [1, 5-c] pyrimidin-5-amine (Cmpd.
  • Step 1 5-dimethyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine
  • the resulting mixture was washed with 3 x10 ml of water and 2 x10 ml of saturated brine. The organic layer was dried over anhydrous sodium sulfate.
  • the crude product (20 mg) was purified by Prep-HPLC with the following conditions: (Column: XBridge Prep OBD C18 Column 19*250mm, 5 ⁇ m; Mobile Phase A: Water (10MMOL/L NH 4 HCO 3 +0.1%NH 3 . H 2 O) , Mobile Phase B: ACN; Flow rate: 20 mL/min) .
  • Step 1 6- ( (5-amino-7- (4-fluorophenyl) -8- (2-methylpyridin-4-yl) - [1, 2, 4] triazolo [1, 5-f] pyrimidin-2-yl ) methyl) picolinonitrile (Cmpd. 19)
  • Step 1 3-dimethyl 2- [3- (difluoromethoxy) pyridin-2-yl] propanedioate
  • Step 4 7-chloro-2- ( (3-fluoropyridin-2-yl) methyl) -8-iodo- [1, 2, 4] triazolo [1, 5-c] pyrimidin-5-amine
  • Desired product could be detected by LCMS.
  • the crude product (50 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep C18 OBD Column, 5 ⁇ m, 19*150 mm; Mobile Phase A: Water (10MMOL/L NH 4 HCO 3 +0.1 %NH 3 .
  • step 5 The crude product (step 5, Cmpd. 22, 40 mg) was purified by Prep-HPLC with the following conditions (Column: X Bridge Prep OBD C18 Column 19*250 mm, 5 ⁇ m; Mobile Phase A: Water (0.05 %NH 3 .
  • 6-bromo-2-methyl-2, 3-dihydropyridazin-3-one (100 mg, 0.53 mmol, 1 equiv) , 4, 4, 5, 5-tetramethyl-2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 3, 2-dioxaborolane (161 mg, 0.63 mmol, 1.20 equiv) , Pd (dppp) Cl 2 (31 mg, 0.1 mmol, 0.10 equiv) in dioxane (10 mL) , KOAc (156 mg, 1.6 mmol, 3.00 equiv) .
  • Step 2 6- (5-amino-7- (4-fluorophenyl) -2- ( (3-fluoropyridin-2-yl) methyl) - [1, 2, 4] triazolo [1, 5-f] pyrimi din-8-yl) -2-methylpyridazin-3 (2H) -one (Cmpd. 30)
  • the resulting mixture was stirred for 15 hours at 80°C under nitrogen atmosphere.
  • the resulting mixture was concentrated under vacuum.
  • the crude product was purified by Prep-HPLC with the following conditions: Column, XBridge RP, 30*150 mm, 5 ⁇ m; Mobile Phase A: Water (0.1%NH 4 HCO 3 ) , Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 16%B to 45 %B in 8 min; 254/220 nm; Rt: 6.12 min.
  • the crude product (50 mg) was purified by Prep-HPLC with the following conditions (Column: X Bridge Prep OBD C18 Column 30 ⁇ 150 mm 5 ⁇ m; Mobile Phase A: Water (0.05 %NH 3 . H 2 O) , Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 25%B to 40%B in 7 min; 254, 220 nm; Rt: 6.35 min) to afford 2- [ (3-fluoropyridin-2-yl) methyl] -8- [imidazo [1, 2-a] pyridin-6-yl] -7- (1, 3-oxazol-2-yl) - [1, 2, 4] triazolo [1, 5-c] pyrimidin-5-amine (Cmpd.
  • the crude product (50 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column 30 ⁇ 150 mm 5 ⁇ m; Mobile Phase A: Water (0.05 %NH 3 H 2 O) , Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30%B to 40%B in 7 min; 254, 220 nm; Rt: 5.9 min) to afford 2- [ (2, 6-difluorophenyl) methyl] -8- (2, 6-dimethylpyridin-4-yl) -7- (1, 3-oxazol-2-yl) - [1, 2, 4] triazolo[1, 5-c] pyrimidin-5-amine (Cmpd.
  • the crude product (20 mg) was purified by Prep-HPLC with the following conditions (Column: X Bridge Prep OBD C18 Column 30 ⁇ 150 mm 5 ⁇ m; Mobile Phase A: Water (10 MMOL/LNH 4 HCO 3 +0.1 %NH 3 . H 2 O) to afford 5- [5-amino-7- (4-fluorophenyl) -2- [ (3-fluoropyridin-2-yl) methyl] - [1, 2, 4] triazolo [1, 5-c] pyrimi din-8-yl] -1-ethyl-1, 2-dihydropyridin-2-one (Cmpd. 34) (2.0 mg) as a white solid.
  • Step 1 6- [ [5-amino-7- (4-fluorophenyl) -8- [imidazo [1, 2-a] pyridin-6-yl] - [1, 2, 4] triazolo [1, 5-c] pyrimidi n-2-yl] methyl] pyridin-2-amine
  • the crude product (100 mg) was further purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column 30 ⁇ 150 mm 5 ⁇ m; Mobile Phase A: Water (0.05 %NH 3 H 2 O) , Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 25%B to 35%B in 7 min; 254/220 nm; Rt: 6.1 min) to afford 2- ( (6-aminopyridin-2-yl) methyl) -7- (4-fluorophenyl) -8- (imidazo [1, 2-a] pyridin-6-yl) - [1, 2, 4] triazolo [1, 5-c] pyrimidin-5-amine (Cmpd.
  • Step 2 7- (4-fluorophenyl) -2- ( (3-fluoropyridin-2-yl) methyl) -8- (2- (methylamino) pyridin-4-yl) - [1, 2, 4] triazolo [1, 5-c] pyrimidin-5-amine (Cmpd. 43)
  • Step 8 Preparation of 7- (4-fluorophenyl) -2- ( (6-methylpyridin-2-yl) methyl) -8- (2-methylpyridin-4-yl) - [1, 2, 4] triazol o [1, 5-c] pyrimidin-5-amine (Cmpd. 45)
  • Desired product could be detected by LCMS.
  • the resulting mixture was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 /MeOH (20: 1) to afford crude product 450 mg. It was dissolved in DCM/EtOH (1/1, 10 mL) , then DCM was removed under reduced pressure, the precipitated solids were collected by filtration and washed with EtOH (2 x 5 mL) , to afford 5- (5-amino-7- (4-fluorophenyl) -2- ( (3-fluoropyridin-2-yl) methyl) - [1, 2, 4] triazolo [1, 5-c] pyrimidin-8-yl) -1-isopropylpyridin-2 (1H) -one (Cmpd.
  • the residue/crude product was purified by reverse phase flash with the following conditions (column, C18 silica gel; mobile phase, MeOH in water, 10%to 50%gradient in 10 min; detector, UV 254 nm) to afford 5- [5-amino-7- (4-fluorophenyl) -2- [ (1, 3-thiazol-4-yl) methyl] - [1, 2, 4] triazolo [1, 5-c] pyrimidin-8 -yl] -1-methyl-1, 2-dihydropyridin-2-one (Cmpd. 58) (10 mg, 23.37%) as an off-white solid.
  • Step 1 1- (1, 1-dioxidothietan-3-yl) -5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2 (1H) -one
  • Step 2 1, 6-dimethyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2 (1H) -one.

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Abstract

La présente invention concerne de nouveaux composés de triazolo-pyrimidine ciblant des récepteurs d'adénosine (en particulier a1 et a2, en particulier a2a). La présente invention concerne également des compositions pharmaceutiques comprenant un ou plusieurs des composés en tant que principe actif, et l'utilisation des composés dans le traitement du récepteur de l'adénosine (AR) par exemple le cancer tel que le NSCLC, le RCC, le cancer de la prostate et le cancer du sein.
PCT/CN2019/105591 2018-09-12 2019-09-12 Composés de triazolo-pyrimidine et leurs utilisations WO2020052631A1 (fr)

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CN201980006436.2A CN111601809A (zh) 2018-09-12 2019-09-12 三唑并-嘧啶化合物和其用途
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EP19859380.8A EP3849983A4 (fr) 2018-09-12 2019-09-12 Composés de triazolo-pyrimidine et leurs utilisations
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WO2021156439A1 (fr) 2020-02-06 2021-08-12 Astrazeneca Ab Composés de triazole utiles en tant qu'antagonistes du récepteur de l'adénosine
US11161850B2 (en) 2018-07-05 2021-11-02 Incyte Corporation Fused pyrazine derivatives as A2A / A2B inhibitors
US11168089B2 (en) 2018-05-18 2021-11-09 Incyte Corporation Fused pyrimidine derivatives as A2A / A2B inhibitors
US11220510B2 (en) 2018-04-09 2022-01-11 Incyte Corporation Pyrrole tricyclic compounds as A2A / A2B inhibitors
CN114585625A (zh) * 2019-08-26 2022-06-03 因赛特公司 作为a2a/a2b抑制剂的三唑并嘧啶
US11390624B2 (en) 2019-01-29 2022-07-19 Incyte Corporation Pyrazolopyridines and triazolopyridines as A2A / A2B inhibitors
US11673894B2 (en) 2018-02-27 2023-06-13 Incyte Corporation Imidazopyrimidines and triazolopyrimidines as A2A / A2B inhibitors

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TWI820209B (zh) * 2018-09-12 2023-11-01 大陸商迪哲（江蘇）醫藥股份有限公司 三唑并－嘧啶化合物及其用途
KR20210116550A (ko) 2019-01-18 2021-09-27 누베이션 바이오 인크. 아데노신 길항제로서의 헤테로시클릭 화합물
CA3126931A1 (fr) 2019-01-18 2020-07-23 Nuvation Bio Inc. Composes de 1,8-naphthyridinone et leurs utilisations

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11673894B2 (en) 2018-02-27 2023-06-13 Incyte Corporation Imidazopyrimidines and triazolopyrimidines as A2A / A2B inhibitors
US11220510B2 (en) 2018-04-09 2022-01-11 Incyte Corporation Pyrrole tricyclic compounds as A2A / A2B inhibitors
US11168089B2 (en) 2018-05-18 2021-11-09 Incyte Corporation Fused pyrimidine derivatives as A2A / A2B inhibitors
US11873304B2 (en) 2018-05-18 2024-01-16 Incyte Corporation Fused pyrimidine derivatives as A2A/A2B inhibitors
US11161850B2 (en) 2018-07-05 2021-11-02 Incyte Corporation Fused pyrazine derivatives as A2A / A2B inhibitors
US11999740B2 (en) 2018-07-05 2024-06-04 Incyte Corporation Fused pyrazine derivatives as A2A / A2B inhibitors
US11390624B2 (en) 2019-01-29 2022-07-19 Incyte Corporation Pyrazolopyridines and triazolopyridines as A2A / A2B inhibitors
US11884665B2 (en) 2019-01-29 2024-01-30 Incyte Corporation Pyrazolopyridines and triazolopyridines as A2A / A2B inhibitors
CN114585625A (zh) * 2019-08-26 2022-06-03 因赛特公司 作为a2a/a2b抑制剂的三唑并嘧啶
WO2021156439A1 (fr) 2020-02-06 2021-08-12 Astrazeneca Ab Composés de triazole utiles en tant qu'antagonistes du récepteur de l'adénosine

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US20210009600A1 (en) 2021-01-14
EP3849983A1 (fr) 2021-07-21
US10858365B2 (en) 2020-12-08
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BR112021004774A2 (pt) 2021-08-03
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CN112279852B (zh) 2023-01-17
CN112279852A (zh) 2021-01-29

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